Glushakov A V, Dennis D M, Morey T E, Sumners C, Cucchiara R F, Seubert C N, Martynyuk A E
Department of Anesthesiology, University of Florida, Gainsville, FL 32610-0254, USA.
Mol Psychiatry. 2002;7(4):359-67. doi: 10.1038/sj.mp.4000976.
Hippocampal N-methyl-D-aspartate receptors (NMDARs) are thought to be involved in the regulation of memory formation and learning. Investigation of NMDAR function during experimental conditions known to be associated with impaired cognition in vivo may provide new insights into the role of NMDARs in learning and memory. Specifically, the mechanism whereby high concentrations of L-phenylalanine (L-Phe) during phenylketonuria (>1.2 mM) cause mental retardation remains unknown. Therefore, the effects of L-Phe on NMDA-activated currents (I(NMDA)) were studied in cultured hippocampal neurons from newborn rats using the patch-clamp technique. L-Phe specifically and reversibly attenuated I(NMDA) in a concentration-dependent manner (IC(50) = 1.71 +/- 0.24 mM). In contrast, L-tyrosine (L-Tyr), an amino acid synthesized from L-Phe in normal subjects, did not significantly change I(NMDA). Although the L-Phe-I(NMDA) concentration-response relationship was independent of the concentration of NMDA, it was shifted rightward by increasing the concentration of glycine. Consistent with an effect of L-Phe on the NMDAR glycine-binding site, L-Phe (1 mM) did not attenuate I(NMDA) in the presence of D-alanine (10 microM). Furthermore, L-Phe significantly attenuated neither glutamate-activated current in the presence of MK-801, nor current activated by AMPA. The finding that L-Phe inhibits specifically NMDAR current in hippocampal neurons by competing for the glycine-binding site suggests a role for impaired NMDAR function in the development of mental retardation during phenylketonuria and accordingly an important role for NMDARs in memory formation and learning.
海马体N-甲基-D-天冬氨酸受体（NMDARs）被认为参与记忆形成和学习的调节。在已知与体内认知受损相关的实验条件下研究NMDAR功能，可能会为NMDARs在学习和记忆中的作用提供新的见解。具体而言，苯丙酮尿症期间高浓度的L-苯丙氨酸（L-Phe）（>1.2 mM）导致智力迟钝的机制仍然未知。因此，使用膜片钳技术研究了L-Phe对新生大鼠培养海马神经元中NMDA激活电流（I(NMDA)）的影响。L-Phe以浓度依赖性方式特异性且可逆地减弱I(NMDA)（半数抑制浓度[IC(50)] = 1.71±0.24 mM）。相比之下，正常受试者由L-Phe合成的氨基酸L-酪氨酸（L-Tyr）并未显著改变I(NMDA)。尽管L-Phe-I(NMDA)浓度-反应关系与NMDA浓度无关，但通过增加甘氨酸浓度可使其向右移动。与L-Phe对NMDAR甘氨酸结合位点的作用一致，在存在D-丙氨酸（10 microM）的情况下，L-Phe（1 mM）并未减弱I(NMDA)。此外，在存在MK-801的情况下，L-Phe既未显著减弱谷氨酸激活电流，也未减弱由AMPA激活的电流。L-Phe通过竞争甘氨酸结合位点特异性抑制海马神经元中NMDAR电流这一发现表明，NMDAR功能受损在苯丙酮尿症期间智力迟钝的发展中起作用，因此NMDARs在记忆形成和学习中起重要作用。
